16-ethers and 16,17-cycloborate esters of 16alpha,17alpha-dihydroxyprogesterone and process of preparing



United States Patent Ofilice 3,006,930 Patented Oct. 31, 1961 Thisinvention relates to, and has for its object the provision of, a methodof prepaiing physiologically active steroids, and to the physiologicallyactive steroids produced thereby.

The steroids of this invention include: (a) 16,l7a-dihydroxyprogesteronel6a,l7a-cycloborate; and (b) 16- ethers of the general formula wherein Qis alkyl or aralkyl and Y is hydrogen or the acyl radical of ahydrocarbon carboxylic acid of less than twelve carbon atoms.

The 16a,17a-cycloborate ester of this invention is pre pared byinteracting 16a,17u-dihydroxyprogesterone with boric acid anhydride. Thereaction is preferably carried out by treating a suspension or solutionof the steroid with the boric acid anhydride in an organic solvent, suchas methanol, at an elevated temperature, such as the reflux temperatureof the organic solvent.

The ethers of this invention are prepared by interacting the cycloborateester with a diazo compound of the formula, Q'N wherein Q is alkylideneor aralkylidene, preferably of less than ten carbon atoms as exemplifiedby the lower alkylidenes e. g. diazomethane and diazoethane) and themonocyclic ar(lower alkylidenes) (e.g. phenyldiazomethane) The reactionis conducted in the presence of water or an alcohol, such as a loweralkanol, at any normal temperature, such as ambient temperature.

The resulting free l7a-hydroxyl compound (Y is hydrogen) can then beesterified by treating with an acid anhydride or acyl halide in an inertsolvent (e.g. benzene) in the presence of an acid catalyst (e.g.patoluenesulfonic acid). Among the suitable reactants for this reactionmay be mentioned the anhydrides of hydrocarbon carboxylic acids havingless than twelve carbon atoms, as exemplified by the lower alkanoicacids (e.g., acetic, propionic and hexanoic acids), the monocyclicaromatic carboxylic acids (e.g. benzoic acid), the monocyclic aralkanoicacids (e.g. phenacetic and fi-phenylpropionic acids), the lower alkenoicacids, the lower cycloalkane carboxylic acids, and the lower cycloalkenecarboxylic acids.

All of the compounds of this invention are physiologically-activesubstances which possess progestational activity and hence can be usedin lieu of known progestational agents in the treatment of such diseasesand conditions as habitual or threatened abortion, amenorrhea andpremenstrual tension, for which purpose they are administered in thesame manner as progesterone, for example, the dosage being adjusted forthe relative potency of the particular steroid.

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 160a,] 7a-dihydroxy progesterone 160a,] 7a-cycloborate Asolution of 500 mg. of 16a,l7a-dihydroxyprogesterone and 2.5 g. of borontrioxide in 25 ml. of methanol is refluxed for 1 hour. After cooling,the solution is concentrated to a volume of 20 ml. in vacuo and 40 ml.of water is added. The resulting precipitate of the cycloborate isremoved by filtration.

EXAMPLE 2 1 6 a-meth oxy 7 a-hy droxy progesflerone To a solution of mg.of 16a,17a-dihydroxyprogesterone cycloborate in 2 ml. of methanol isadded suflicient ethereal diazomethane to maintain a yellow color. Afterremoval of the solvents in vacuo the residue is taken up in chloroformand water, the chloroform washed with water and the solvent removed invacuo. The residual l6a-methoxy-17a-hydroxyprogesterone afterrecrystallization from 95% ethanol has the following properties: M.P.about 142143; [a] -|60 (c, 0.15 in chlf.);

mg, 234 m (e=15,400); Ami? 2.92, 5.88, 5.98, 6.20 p

Analysis.Calcd. for C H O (360.48): C, 73.30; H, 8.95; OMe, 8.60. Found:C, 73.06; H, 8.89; OMe, 7.89.

EXAMPLE 3 1 6ot-eth0xy-1 7 a-hydroxy progesterone Substituting anequivalent amount of diazoethane for the diazomethane in Example 2,there is obtained 16aethoxy-17a-hydroxyprogesterone.

Similarly, by substituting diazophenylmethane for the diazomethane inExample 2, there is obtained 16a-benzyloxy-17oc-hydroxypr0gesterone.

EXAMPLE 4 16a-meth0xy-1 7 a-hydroxyprogesterone caproate A mixture of300 mg. of 16a-methoxy-17u-hydroxyprogesterone, 16 mg. ofp-toluenesulfonic acid, mono hydrate, 0.5 ml. of hexanoic anhydride and10 ml. of dry benzene is heated at 80 until a clear solution isobtained. The mixture is allowed to remain at room temperature for 22hours, after which time ice is added and the excess anhydride isdecomposed by stirring for two hours at room temperature. The mixture istaken up in chloroform, extracted with water and dilute bicarbonate andagain with water. The chloroform solution is then dried over sodiumsulfate and the solvent removed in vacuo. The residue represents the17-caproate of 16amethoxy-l7a-hydroxyprogesterone.

EXAMPLE 5 16a-meth0xy-l 7 a-hydroxyprogesterone acetate Using theconditions of Example 4 but substituting 0.4 ml. of acetic anhydride forthe hexanoic anhydride used in Example 4 there is obtained theHot-acetate of methoxy-17a-hydroxyprogesterone.

Similarly, by substituting 1fia-ethoxy-lh-hydroxyprogesterone and16a-benzyloxy-l7a-hydroxyprogesterone for the steroid in the proceduresof Examples 4 and 5, 16ozethoxy-l7u-hydroxyprogesterone caproate,l6a-ethoxy- 17a-hydroxyprogesterone aceate, 16ot-b6I1ZYlOXY-17oc-hY-droxyprogesterone caproate and l6a-benzyloxy-l7a-hydroxyprogesteroneacetate are obtained respectively.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. 16a,l7a-dihydroxyprogesterone 16a,17a-cycloborate.

3 2. A steroid of the general formula I Cli wherein Q is selected fromthe 'group consisting of alkyl of less than ten carbon atoms and aralkylof less than ten carbon atoms and Y is selected from the groupconsisting of hydrogen and the acyl radical of a hydrocarbon carboxylicacid of less than twelve carbon atoms.

3. 16a-(lower alkoxy)-l7a-hydroxyprogesterone.

4. The ester of l6a-(lower alkoxy)-l7 a-hydroxyprogesterone with ahydrocarbon 'carboxylic acid of less than twelve carbon atoms,

5. 16a methoXy-17a-hydroxyprogesterone.

6'. 16a-eth'oXy-l7q-hydroxyprogesterone.

7. l'6d-rnethoxy-l7a-hydroxyprogesterone caproate.

8. 16ix-methoxy-l7a-hydroxyprogesterone acetate.

9. A process for preparing a steroid of the general formula wherein Q isselected from the group consisting of alkyl of less than ten carbonsatoms and aralkyl of less than ten carbon atoms, which comprisesinteracting 16a,17oc-dihy droxyprogesterone 16a,17a-cycloborate with acompound selected from the group consisting of diazoalkane anddiazoaralkane, wherein the alkane and aralkane radicals have less thanten carbon atoms, in the presence of a compound selected from the groupconsisting of Water and lower alkanol, and recovering the 16u-etherformed.

10. A process for preparing the 17a-esters of a compound selected fromthe group consisting of 16a-alkoxy- 17u-hydroxyprogesterone andl6a-aralkoxy-l7a-hydroxyprogesterone with hydrocarbon carboxylic acidsof less than twelve carbon atoms, which comprises interacting a compoundselected from the group consisting of 16aalkoxyl7a-hydroxyprogesteroneand 16a-aralkoxy-17ahydroxyprogesterone with a compound selected fromthe group consisting of the acid anhydrides and acyl halides of ahydrocarbon carboxylic acid having less than twelve carbon atoms, in thepresence of an acid catalyst.

References Cited in the file of this patent UNITED STATES PATENTS2,183,589 Reichstein et al. Dec. 19, 1939 2,716,125 Hirschmann et alAug. 23, 1955 2,727,909 Colton Dec. 20, 1955 2,753,360 Kaspar et al.July 3, 1956 2,831,003 Thomas Apr. 15, 1958 UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Josef Fried It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 3, lines 2 to 12, shown below instead of as the formula shouldappear as in the patent:

Signed and sealed this- 8th day of May 1962.

(SEAL) Attest:

DAVID L. LADD Commissioner of Patents ERNEST W. SWIDER Attesting Officer

1. 16A, 17A-DIHYDROXYPROGESTERONE 16A,17A-CYCLOBORATE.